Aconitine is an alkaloid neurotoxin that is produced by various species of the genus Aconitum, such as wolfsbane and monkshood. Despite its toxicity, aconitine has seen a limited use as a medicine since its discovery, for example in the treatment of neuralgia, fever, pericarditis, and nervous palpitation. Calculation of an appropriate dosage is difficult, however, due to the narrow therapeutic index. Aconitine is known to open tetrodotoxin (TTX)-sensitive sodium channels in the heart and other tissues, and it has been used to create models of cardiac arrhythmia. See, for example, Wang and Wang Cellular Signaling 2003, 15, 151-159.

The structure of aconitine was determined over fifty years ago (Wiesner et al. Tetrahedron Lett. 1959, 2, 15) and various semisynthetic modifications of the molecule have been reported. For example, U.S. Pat. No. 5,770,604 reports the modification of aconitine by hydrolysis of the C-14 benzoate moiety and subsequent acylation of the resulting C-14 hydroxyl group with various modified benzoyl groups. The initial hydrolysis step is not selective, however, and the resulting aconine compounds lack the acetyl group on the C-8 hydroxyl that is normally found in the natural product.
Likewise, U.S. Pat. Nos. 5,478,833; 5,478,834; 5,496,825; and 5,770,604 report the modification of known aconitine alkaloids, such as aconitine, mesaconitine, hypaconitine, and jesaconitine, and various aconine compounds lacking the C-8 acetyl group, by deoxygenation at positions 3, 8, 13, or 15, or by replacement of substituents at the ring nitrogen or at positions 1, 8, or 14. These reactions show limited selectivity, however, and do not allow for targeted substitution at the C-8 and C-14 positions of the natural aconitine structure.
Borcsa et al., Fitoterapia 2011, 82, 365-368, provide the semisynthesis and pharmacological investigation of lipo-alkaloids prepared from aconitine. According to the reported methods, the acetyl group at C-8 is transesterified with fatty acyl moieties. No modification of the C-14 benzoyl group was reported, however.
The rearrangement reactions of aconitine and other related diterpenoid and norditerpenoid alkaloids have been reviewed. See Pelletier, J. Natural Prod. 1992, 55, 1-24.
The strong therapeutic potential of aconitine in the treatment of pain and other diseases of the nervous system make it an attractive candidate for structural modification and analysis. There is thus a need for improved compound derivatives of aconitine, pharmaceutical compositions, methods of use, and methods of preparation.